Determining the Impact of Edelfosine on Restoring the Gut Microbiota after and Epileptic Insult

University Of Puerto Rico Med Sciences, San Juan PR

Investigators

Abstract

ABSTRACT Determining the impact of edelfosine on restoring the gut microbiota after an epileptic insult Most anti-epileptic therapies induce significant side effects [1-3], emphasizing the critical need to explore new strategies to treat epilepsy. Recent research indicates a correlation between dysbiosis and central nervous system (CNS) in epilepsy [4,5]. Modulating the gut microbiota in epilepsy patients through probiotics, diet, or fecal matter transplant (FMT) has shown positive effects in patients with epilepsy [6]. Given the role of phospholipase C (PLC) in mediating inflammatory modulation and cytokine production in T-cells and macrophages [7-9], the use of PLC inhibition as an anti-inflammatory strategy is another promising strategy to reduce epileptic seizures. The proposed aims will use edelfosine (Ef), encapsulated in a drug delivery system (DDS), as a PLCβ3 inhibitor [10-12] This project explores whether Ef impacts the gut microbiota and metabolites following an epileptic insult. We will collect fecal matter of naïve animals and epilepsy-induced animals before and after the seizure (2h, 26h, 50h) and analyze gut microbiota, its metabolites, and brain metabolites. We will compare the obtained data in Ef-treated and untreated mice.We hypothesize that Ef will promote an anti-inflammatory microenvironment within the gut by protecting the survival of butyrate-producing taxa such as Bifidobacteria and Lactobacillus after an epileptic insult. The Center for Microbiome Studies (CMS) 16S sequencing and metabolomic cores and mentoring to delve into this new field will be essential to accomplish the proposed 3 aims: 1) Characterize the gut microbiome in an animal model of epilepsy and associate its α- and β-diversity with the effect of Ef. We will compare 16S rRNA sequencing of feces collected before and after an epileptic insult in Ef treated and untreated mice. 2) Identify differences in gut bacterial and brain metabolites associated with lower inflammatory status in Ef-treated versus untreated mice, using GC/MS and LC/MS-based metabolomics in the fecal samples and mouse brains of Aim 1 mice. 3) Characterize if FMTs from Ef-treated mice can increase gut resilience in animals with epilepsy, reducing the severity of seizures. FMT from Ef treated and untreated mice will be gastrointestinally gavaged into naïve mice and 24h later, we will measure and compare seizure activity. Fecal microbiota and metabolomics of feces collected before and after the seizure (2h, 26h, 50h) will be compared. The Center for Microbiome Studies will enable me to generate the data for these 16S sequencing and metabolomic studies, allowing my research area to expand in an innovative direction toward dissecting how specific treatments could impact the gut-brain axis. This center will allow me to build new skills, recruit students to develop their projects, and establish expertise in new areas, strengthening the laboratory's capabilities.